Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy

Abstract

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndrome

“…The OS was 21 months (95% CI 11-32) and 20 months (95% CI [19][20][21][22] for 1L HMA/Venetoclax and 1L HMA alone respectively (p = 0.86) (Fig. 1).…”

“…For this treatment population, the ORR was 61%, CR 13%, and mCR 48%. The median OS from diagnosis for patients who received HMA/Venetoclax for HMA failure MDS was 33 months (95% CI 31-36) compared to 21 months (95% CI 11-32) for those who had 1L HMA/Venetoclax and 20 months (95% CI [19][20][21][22] for those who received 1L HMA alone with no subsequent Venetoclax therapy (p = 0.02) (Figure -3). Nine of 31 patients who received HMA/Venetoclax for R/R MDS underwent AHSCT compared to 22 who did not proceed to transplant with median OS of 31 months and 33 months, respectively (p = 0.70).…”

“…Understanding the stem cell architecture driving MDS, especially in the HMA failure setting, has been evaluated by Ganan-Gomez et al Compared with untreated patients, hematopoietic stem cells (HSC) from patients with HMA failure had signi cantly upregulated genes enhancing cell proliferation and survival. 19 This included the gene anti-apoptotic regulator B-cell lymphoma 2 (BCL-2), the target of Venetoclax, suggesting the response of HMA failure patients to HMA + Venetoclax therapy in this study. Utilizing Venetoclax in the HMA failure setting effectively target these HSCs.…”

“…were able to demonstrate change in a subset of bone marrow stem cells, common myeloid progenitors, after treatment with Venetoclax. 19 Limitations of our study include its retrospective nature, small number of patients treated with HMA Venetoclax combination, short duration of follow up for the combination arm, lack of minimal residual disease assessment, and the physician's bias in administering the combination for selected group of patients. Additionally, no data on dose adjustment and adverse events were collected for this study purpose.…”

Isolation, culture, and immunophenotypic analysis of bone marrow HSPCs from patients with myelodysplastic syndromes

“…Lastly, specific steps are given to quantify surviving cells and assess changes in the HSPC hierarchies. For complete details on the use and execution of this protocol, please refer to Ganan-Gomez et al. (2022) .…”